Inflammation is the coordinated response to tissue injury or infection. Inflammation begins with the local release of chemotactic factors, platelet activation, and initiations of the coagulation and complement pathways. These events stimulate the local endothelium, promoting the extravasation of neutrophils and monocytes. The second phase of inflammation is characterized by the influx into the tissue of cells of the adaptive immune system, including lymphocytes. The subsequent resolution phase, when apoptosis of the excess leukocytes and engulfment by tissue macrophages takes place, is also characterized by repair of tissue damage by stromal cells, such as fibroblasts.
In such repair mechanisms fibroblasts migrate into the affected area and can exhibit an altered phenotype being hyperproliferative or producing excess collagen. Fibroblasts are classically thought of as being predominantly resident cells, however, emerging data has indicated that circulating fibroblast precursor cells, fibrocytes, migrate to the sites of repair or injury, where they differentiate and mediate wound healing, tissue repair and other fibrotic responses, such as pathological fibrosis.
Fibrocytes originate from bone marrow, differentiate from a CD14+ peripheral blood monocyte precursor population and express markers of hematopoietic cells (CD45, MHC class II, CD34), stromal cells (collagen types I and III and fibronectin), as well as chemokine receptors (CCR3, CCR5, CCR7 and CXCR4) (Abe et al., J. Immunol. 166:7556-62, 2001; Moore et al., Am. J. Pathol. 166:675-84, 2005; Bucala et al., Mol. Medicine 1:71-81, 1994). Fibrocytes do not express a variety of endothelial, epithelial or smooth-muscle markers, and are negative for the monocyte/macrophage and dendritic cell specific markers CD4, CD16 and CD25 (Bucala et al., Mol. Med. 1:71-81, 1994; Freudenthal and Steinman PNAS 87:7698-7702, 1990). Thus, an isolated fibrocyte cell is a unique cell type with a defined phenotype readily distinguishable from resident mesenchymal or circulating cells.
Once released from the bone marrow, fibrocyte migration and differentiation into fibroblasts and myofibroblasts is induced by various mediators. CCR2/CCL2, CXCR4/CXCL12, CCR7/CCL21 receptor/ligand pairs have been implicated in the recruitment and accumulation of fibrocytes into tissues during fibrotic processes (Phillips et al., J. Clin. Invest. 114:438-46, 2004; Sakai et al., PNAS 103:14098-103, 2006; Tacke and Randolph, Immunobiology 211:609-18, 2006). TGF-β1, ET-1, PDGF, IL-4 and IL-13 have been shown to promote fibrocyte differentiation into mature fibroblasts and myofibroblasts with acquirement of increased production of collagen and other ECM proteins, downregulation of CD34 and CD45, and expression of the myofibroblast marker α-smooth muscle actin (α-SMA). The in vivo differentiation of fibrocytes from circulating precursors may mainly occur at the tissue site and not in the peripheral blood (Haudek et al., PNAS 103:18284-289, 2006; Frid et al., Am. J. Pathol. 168:659-69, 2006). In addition to production of ECM proteins, fibrocytes secrete inflammatory cytokines (TNF-α and TGF-β), hematopoietic growth factors (IL-6, IL-10, M-CSF), growth factors (TGF-α, VEGF, PDGF-A, HGF, CNTGF, bFGF) and chemokines (CCL2, CCL3, CCL4, CXCL1, CXCL8) (Abe et al., J. Immunol. 166:7556-62, 2001; Chesney et al., J. Immunol. 160:419-25, 2006; Chesney et al., Curr. Rheumatol. Rep. 2:501-5, 2000).
Mature fibrocytes rapidly enter sites of tissue injury where they secrete inflammatory cytokines, extracellular matrix proteins, other cytokines and pro-angiogenic molecules, playing a role in a number of human diseases. Human and mouse studies have demonstrated that fibrocytes from peripheral blood migrate to skin wound chambers (Bucala et al., Mol. Med. 1:71-81, 1994; Chesney et al. J. Immunol. 160:419-25, 1998; Abe et al., J. Immunol. 166:7556-62, 2001) and bronchial mucosa after antigen challenge. Fibrocytes have been reported in disease states with fibrotic pathologies including asthma and idiopathic pulmonary fibrosis (Schmidt et al. J. Immunol. 171:380-89, 2003; Abe et al., Am. J. Prespir. Crit. Care Med. 170:1158-63, 2004; Moore et al. Am. J. Pathol. 166:675-84, 2005), and excessive myofibroblast proliferation is associated with Crohn's disease (Am. J. Physiol. Gastrointest. Liver Physiol. 295:G581-90, 2008). In murine models, fibrocytes have been shown to contribute to the pathogenesis of pulmonary fibrosis and liver fibrosis, in the liver fibrocytes contributing to collagen deposition (Kisselva et al., J. hepatology 45:429-38, 2006; Gomperts and Stierter, J. leukocyte Biol. 82:449-56, 2007). There is evidence for a role for fibrocytes in hypertrophic scars or keloids, burns, scleroderma and related disorders. Fibrocytes may contribute to fibrogenesis in several ways as these cells produce collagen and have been shown to differentiate into a more resident myofibroblast phenotype, which may exacerbate the fibrotic environment even further (Moore et al., Am. J. Pathol. 166:675-84, 2005; Mehrad et al., Biochem. Biophys. Res. Commun. 353:104-8, 2007; Phillips et al., J. Clin. Invest. 114:438-46, 2004; Epperly et al., Am. J. Respir. Cell. Mol. Biol. 29:213-24, 2003; Hashimoto et al., J. Clin. Invest. 113:243-52, 2004; Moore et al., Am. J. Respir. Cell. Mol. Biol. 35:175-81, 2006). Fibrocytes also constitute part of the stromal response to tumor invasion, and these cells may be a prognosticator of malignancy potential (Barth et al., J. Exp. Med. 11:11, 2002; Chauhan et al., J. Clin. Pathol. 56:271-76, 2003). Fibrocyte differentiation into myofibroblasts is also associated with stromal remodeling during invasive carcinomas in the urinary bladder (Nimphius et al., Virchows Arch. 450:179-85, 2007).
The signals that modulate fibrocyte proliferation and differentiation, cytokine and chemokine secretion, and migration are only partially defined. A better understanding of these signals may enable new therapies to prevent human diseases or conditions with altered fibrocyte function, for example pathologic fibrosis. Thus, there is a need to identify and modulate receptor/ligand interactions that mediate fibrocyte functions.